There is very little known about the mechanisms responsible for the very long-term storage of information in the neocortex. Recent studies from our laboratory suggest that besides its role in the hippocampus, the alpha calcium calmodulin kinase II (aCaMKII) is critical for cortical plasticity and for remote memory consolidation in neocortical networks. Here, we propose to use a combination of behavioral neuroscience tools, in vivo time-lapse 2 photon laser scanning microscopy (2P LSM), inducible and region-specific molecular approaches to unravel the role of aCaMKII in cortical memory storage. The specific aims of this proposal are: Specific Aim #1- To determine the function of the anterior cingulate and retrosplinial cortex in remote memory in mice. Our preliminary results indicate that these two structures are required for remote memory. Now we would like to define their roles in this poorly understood memory phase. Specific Aim #2- To determine the role of aCaMKII in anterior cingulate and retrosplinial cortex in remote memory. Our previoous results demonstrated a role for this kinase in remote memory. These studies will be critical to determine where this kinase is needed and how it modulates remote memory. Specific Aim #3- To use time lapse in vivo 2P LSM to uncover the role of aCaMKII in synaptic restructuring in anterior cingulate and retrosplinial cortex, (close collaboration with Dr. Joshua Trachtenberg, a co-Pi in this proposal and a pioneer in the ground breaking 2P LSM). There is extensive evidence that CAMKII modulates synaaptic retructuring. Now, we would to characterize these events in vivo and test their impact on remote memory. The experiments proposed here represent some of the first steps in the study of the molecular and cellular mechanisms underlying the storage of memories in cortical networks. Besides their impact on the understanding of remote memory, the results from these studies will be important to understand cognitive disorders associated with age-related cognitive decline and progressive neurodegenerative disorders such as Alzheimer's disease, since these conditions affect the regions and the memory processes that we propose to study.